- Screening of small molecules attenuating biofilm formation of Acinetobacter baumannii by inhibition of ompA promoter activity
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Seok Hyeon Na , Hyejin Jeon , Man Hwan Oh , Yoo Jeong Kim , Je Chul Lee
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J. Microbiol. 2021;59(9):871-878. Published online August 27, 2021
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DOI: https://doi.org/10.1007/s12275-021-1394-z
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Anti-virulence therapeutic strategies are promising alternatives
against drug-resistant pathogens. Outer membrane
protein A (OmpA) plays a versatile role in the pathogenesis
and antimicrobial resistance of Acinetobacter baumannii.
Therefore, OmpA is an innovative target for anti-virulence
therapy against A. baumannii. This study aimed to develop
a high-throughput screening (HTS) system to discover small
molecules inhibiting the ompA promoter activity of A. baumannii
and screen chemical compounds using the bacterial
growth-based HTS system. The ompA promoter and open
reading frame of nptI fusion plasmids that controlled the
expression of nptI encoding resistance to kanamycin by the
ompA promoter were constructed and then transformed into
A. baumannii ATCC 17978. This reporter strain was applied
to screen small molecules inhibiting the ompA promoter
activity in a chemical library. Of the 7,520 chemical compounds,
15 exhibited ≥ 70% growth inhibition of the report
strain cultured in media containing kanamycin. Three compounds
inhibited the expression of ompA and OmpA in the
outer membrane of A. baumannii ATCC 17978, which subsequently
reduced biofilm formation. In conclusion, our reporter
strain is useful for large-scale screening of small molecules
inhibiting the ompA expression in A. baumannii. Hit
compounds identified by the HTS system are promising scaffolds
to develop novel therapeutics against A. baumannii.
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Citations
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- Mutational inactivation of OprD in carbapenem-resistant Pseudomonas aeruginosa isolates from Korean hospitals
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Chi Hyun Kim , Hee Young Kang , Bo Ra Kim , Hyejin Jeon , Yoo Chul Lee , Sang Hwa Lee , Je Chul Lee
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J. Microbiol. 2016;54(1):44-49. Published online January 5, 2016
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DOI: https://doi.org/10.1007/s12275-016-5562-5
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1,464
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Abstract
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This study investigated the mechanisms underlying the carbapenem
resistance of bloodstream isolates of Pseudomonas
aeruginosa obtained from two Korean hospitals. Of the 79
P. aeruginosa isolates, 22 and 21 were resistant to imipenem
and meropenem, respectively. The 22 imipenem-resistant
P. aeruginosa isolates were classified into 7 sequence types
(STs) and 13 pulsotypes. Twelve imipenem-resistant isolates
from one hospital were found to belong to the international
clone ST111. Two imipenem-resistant P. aeruginosa ST235
isolates carried the blaIMP-6 gene, but the remaining 20 isolates
did not produce carbapenemases. Mutations in the oprD
gene and a related decrease in gene expression were found
in 21 and 5 isolates, respectively. However, all imipenemresistant
P. aeruginosa isolates showed no significant expression
of OprD in the outer membrane as compared with that
of carbapenem-susceptible PAO1 strain. Overexpression of
genes associated with efflux pumps, including mexB, mexD,
mexF, and mexY, was not found in any imipenem-resistant
isolate. One imipenem-resistant P. aeruginosa isolate overexpressed
the ampC gene. Our results show that the low permeability
of drugs due to the mutational inactivation of OprD
is primarily responsible for carbapenem resistance in bloodstream
isolates of P. aeruginosa from Korean hospitals.
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